Severe viral hemorrhagic fever caused by Ebola virus (EBOV).
Highest mortality rate of all viral haemorrhagic fevers (25-90%)
Epidemiology
History:
The first recognized Ebola outbreak occurred in 1976, near the Ebola River in Zaire (now Democratic Republic of Congo, DRC). Over the past 40 years, more than 20 outbreaks have occurred in Africa, with most of the known outbreaks occurring in the past 20 years. Before the 2014 epidemic, over 2300 cases with greater than 1500 deaths had been documented from this disease. The current outbreak in West Africa has so far affected more people than all previous Ebola outbreaks combined: as of January 20, 2015, the cumulative number of probable, suspect and laboratory-confirmed cases attributed to Ebola virus was more than 21,000, with greater than 8500 deaths. These numbers likely represent underestimates of the outbreak’s true size because of poor local health system infrastructure, with many patients being cared for outside hospital settings, or not reported.
The map shows the location and years of all reported Ebola virus disease (EVD) outbreaks. Two cases of laboratory-acquired EVD occurred in Russia (not shown) | Kuhn, J. H. in Harrison’s principles of internal medicine Vol. 2 Ch. 205 (eds J. Larry Jameson et al.) (McGraw-Hill Education, 2018).
Transmission:
EVD outbreaks typically start from a single case of probable zoonotic transmission, followed by human-to-human transmission via direct contact or contact with infected bodily fluids or contaminated fomites.
Animal-to-human transmission: Occurs through handling bush meat or direct contact with infected nonhuman primates (such as chimpanzees, gorillas, fruit bats, and monkeys).
Human-to-human transmission: Direct contact via blood and body fluids (including but not limited to urine, feces, vomitus, saliva and sweat) through breaks in the skin or through inoculation into the mouth, nose or eyes.
Virology
Filoviruses:
To date, 12 distinct filoviruses have been described. Ebolaviruses are negative stranded RNA viruses that belong to the Filoviridae family and are endemic to regions of west and equatorial Africa.
Filovirus taxonomy and Ebola virus transmission: a | Taxonomy of the genus Ebolavirus. Thus far, five ebolaviruses have been associated with human infections, and four of them have been identified as pathogens. b | The natural reservoir host(s) of Ebola virus (EBOV) has (have) yet to be identified. Multiple data indicate a direct or indirect role of bats in EBOV ecology, but to date, EBOV has not been isolated from, nor has a near-complete EBOV genome been detected in any wild animal. However, it is tempting to speculate that Ebola virus disease (EVD) is a zoonosis (that is, an infectious disease caused by an agent transmitted between animals and humans) because retrospective epidemiological investigations have often been able to track down the probable index cases of EVD outbreaks. These individuals had been in contact with wild animals or had handled the carcass of a possible accidental EBOV host. c | Scanning electron microscopic (SEM) image of EBOV particles (green) budding from grivet cells. d | Transmission electron microscopic (TEM) image of EBOV particles (green) budding from grivet cells. aThe kingdom name has been approved by the International Committee on Taxonomy of Viruses (ICTV) but has yet to be ratified. | Parts a, b: Jacob, S.T., Crozier, I., Fischer, W.A. et al. Ebola virus disease. Nat Rev Dis Primers 6, 13 (2020). https://doi.org/10.1038/s41572-020-0147-3 | Parts c & d: J. Wada and J. Bernbaum, NIH/NIAID Integrated Research Facility at Fort Detrick, Frederick, MD, USA.
Ebola virus (EBOV):
Ebolaviruses belong to the genus Ebolavirus of the family Filoviridae in the order Mononegavirales, viruses whose genome consists of a single strand of RNA with negative polarity
Electron micrograph of an Ebola virus virion appearing as a ‘bowl of spaghetti’ | CDC/Cynthia Goldsmith – Public Health Image Library (PHIL), #10816
Pathophysiology
Conceptualized EVD pathogenesis | Ebola virus particles enter the body through dermal injuries (microscopic or macroscopic wounds) or via direct contact via mucosal membranes. Primary targets of infection are macrophages and dendritic cells. Infected macrophages and dendritic cells migrate to regional lymph nodes while producing progeny virions. Through suppression of intrinsic, innate and adaptive immune responses, systemic distribution of progeny virions and infection of secondary target cells occur in almost all organs. Key organ-specific interactions occur in the gastrointestinal tract, liver and spleen, with corresponding markers of organ injury or dysfunction that correlate with human disease outcome. The question marks indicate speculated manifestations. RIG-I, antiviral innate immune response receptor RIG-I. | Jacob, S.T., Crozier, I., Fischer, W.A. et al. Ebola virus disease. Nat Rev Dis Primers 6, 13 (2020). https://doi.org/10.1038/s41572-020-0147-3
Clinical features
Characterized by fever, gastrointestinal signs and multiple organ dysfunction syndrome. The incubation period is typically 8–10 days (range, 2–21 days, though it may be shorter when transmission has occurred through contaminated injection needles).
Pathogenesis of Ebola virus disease: Ebola viruses penetrate the human body through mucous membranes, skin lacerations/tear, close contact with infected patients/corpse, or by direct parental dissemination. EBOV has a predilection to infect various cells of immune system (dendritic cells, monocytes, and macrophages), endothelial and epithelial cells, hepatocytes, and fibroblasts where it actively replicates by gene modulation and apoptosis and demonstrate significantly high viremia. The virus reaches the regional lymph nodes causing lymphadenopathy and hematogenous spread to the liver and spleen promote an active inflammatory response. Release of chemical mediators of inflammation (cytokines and chemokines) causes a dysregulated immune response by disrupting the vasculature system harmony, eventually causing disseminated intravascular coagulation and multiple organ dysfunction. | Hasan, S., Ahmad, S. A., Masood, R., & Saeed, S. (2019). Ebola virus: A global public health menace: A narrative review. Journal of family medicine and primary care, 8(7), 2189–2201. https://doi.org/10.4103/jfmpc.jfmpc_297_19
Non-specific features:
Abrupt onset of fever, chills, malaise, anorexia, severe headache and myalgias of the trunk and lower back
Diffuse maculopapular rash by days 5–7 of illness, mainly on the trunk.
Gastrointestinal symptoms:
Occur several days after the initial nonspecific presentation and become the predominant clinical feature
Vomiting, nausea, watery diarrhea and abdominal pain
Bleeding disorders (< 50% cases):
Petechia, bruising, oozing from venipuncture sites and/or mucosal hemorrhage
Conjunctival injection and dark red discoloration of the soft palate are common physical findings
Central nervous system involvement:
Somnolence, delirium, seizures or coma.
Pregnant women:
EBOV can be transmitted transplacentally and also lead to fetal death related to placental insufficiency. EBOV RNA has been detected at high concentrations in amniotic fluid, placenta, fetal tissue and breast milk
Miscarriage/stillbirths
Newborn rarely survive
Higher risk for severe illness and death
Clinical sequelae in survivors of EVD: Clinical sequelae in survivors of Ebola virus disease (EVD) that are supported by evidence that includes physical examination of the individuals. Studies reporting patient-reported symptoms are not included in this summary figure. EBOV, Ebola virus; PTSD, post-traumatic stress disorder. aIn the PREVAIL III clinical trial, a prospective, controlled study assessing symptoms in survivors that had a >10% increase in prevalence compared with control close contacts, this symptom had an increased odds ratio (P < 0.0001) compared with close contact controls. bIn the PREVAIL III clinical trial, in which symptoms in survivors were compared with symptoms in control close contacts (regardless of any increase in their prevalence in survivors), this symptom had an increased odds ratio (P < 0.01) compared with control close contacts. cData from uncontrolled cohorts, case series or case reports. dMost common abnormalities in neurological examinations are abnormal oculomotor examination, abnormal reflexes, tremor and abnormal sensory examination. eMost common abnormalities include irregular heart rate, cardiac murmur, decreased breath sounds, rales (crackling lung sounds) and wheezes. fMost common abnormalities include abdominal tenderness, mass or distension. gMost common abnormalities include muscle tenderness and decreased range of motion. | Jacob, S.T., Crozier, I., Fischer, W.A. et al. Ebola virus disease. Nat Rev Dis Primers 6, 13 (2020). https://doi.org/10.1038/s41572-020-0147-3
Complications:
In nonfatal cases, patients improve typically 6–11 days from onset of symptoms. Fatal disease is associated with more severe clinical signs early in infection
Progression to: Disseminated intravascular coagulation (DIC), septic shock, multiorgan failure
Death usually occurs between 6 and 16 days (mostly around the 9th day) after symptom onset.
Case study:
Diagnosis
Diagnosis requires a combination of case definition and laboratory tests, typically real-time reverse transcription PCR to detect viral RNA or rapid diagnostic tests based on immunoassays to detect EBOV antigens.
Serodiagnosis:
Reverse transcriptase polymerase chain reaction (RT-PCR): Detects viral RNA in blood samples of infected patients immediately after commencement of signs and symptoms
Enzyme-linked immunosorbent assay (ELISA): Detects IgG & IgM in samples of infected patients
Conceptualized clinical course of acute EVD over time: The time course of the clinical manifestations (top), laboratory findings (middle) and viraemia and immune responses (bottom) in patients with Ebola virus disease (EVD). The coloured lines in the top and middle panels do not have defined start and end points as these may vary. Renal dysfunction is common and not well-characterized in patients with EVD; it is probably a multifactorial combination of hypovolaemia (related to gastrointestinal fluid losses, decreased fluid input, fever, hypoalbuminaemia and sepsis pathophysiology), intrinsic renal injury (acute tubular necrosis related to myoglobin pigment injury secondary to rhabdomyolysis or direct viral infection of tubular epithelial cells) or cytokine-mediated nephrotoxicity. Whereas respiratory symptoms and signs may reflect respiratory compensation for a primary metabolic acidosis, primary causes of hypoxaemic respiratory failure include acute lung injury (related to systemic inflammatory response syndrome and/or sepsis or Ebola virus (EBOV)-related cytokinaemia), pulmonary oedema (in the setting of capillary leak or direct infection) and viral pneumonia. Respiratory muscle fatigue may also contribute to ventilatory respiratory failure. Haemorrhagic manifestations include oozing from venepuncture sites, haemoptysis (coughing up blood), haematemesis (vomiting blood), melaena (dark stools as a result of bleeding) and vaginal bleeding. Neurological manifestations include meningoencephalitis and cerebrovascular accidents (such as strokes). ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CPK, creatine phosphokinase; Hb, haemoglobin; HCT, haematocrit; PLT, platelet; PMN, polymorphonuclear leukocyte; PT, prothrombin time; PTT, partial thromboplastin time; WBC, white blood cell count. aIncubation periods of 2–21 days have been reported. | Top panel: Jacob, S.T., Crozier, I., Fischer, W.A. et al. Ebola virus disease. Nat Rev Dis Primers 6, 13 (2020). https://doi.org/10.1038/s41572-020-0147-3 | Bottom panel: Ploquin, A., Zhou, Y. & Sullivan, N. J. Ebola immunity: gaining a winning position in lightning chess. J. Immunol. 201, 833–842 (2018). Detailed review of the “timing is everything” host–pathogen arms race after EBOV infections in humans and non-human primates.
Differential diagnosis:
Initial nonspecific symptoms can be mistaken for other,
Other infections with exanthems: Measles or meningococcemia
Management
Till date, there is no precise antiviral management or vaccination for EVD. Management protocol mainly relies on supportive and symptomatic therapy. Public health strategies emphasizing on epidemiological surveillance, contact tracing, and quarantine of the patient have been recommended to combat the dissemination of EVD.
Supportive management:
IV fluids and oral rehydration solution: Electrolyte substitute and maintain the intravascular volume
Antiemetics and antidiarrheal drugs (for unrelenting vomiting and diarrhea)
Adequate nourishment
Analgesics
Blood transfusion
Prophylactic antibiotics (third generation IV cephalosporins (secondary bacterial infections and septicemia)
Summary:
Ebola virus disease has a high case–fatality rate; there are no approved specific medical countermeasures, but adequate supportive and intensive care can improve outcomes. | Ebola virus disease. Nat Rev Dis Primers 6, 14 (2020). https://doi.org/10.1038/s41572-020-0154-4
